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Principal Investigator: Francesca Demichelis
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2024
Award: $649,486
Funding agency: National Cancer Institute
ABSTRACT - The focus of this proposal is on lethal, metastatic prostate cancer (PC). The aim of this study
is to develop an innovative, minimally invasive, liquid biopsy assay that can be used to identify molecular
subtypes of lethal prostate cancer PC in patients with a biologically aggressive disease. Phenotyping Large
Oncosomes for Ultimate Evaluation of Patients Status (PLUS) will identify biomarkers of short/long response to
treatment, and progressively assess tumor phenotype during PC evolution and under treatment pressure. We
propose to focus on extracellular vesicles (EV) known as large oncosomes (LO) that are identified in the plasma
of patients with aggressive cancer. Using gold standard methods, we obtained pure populations of LO and
performed extensive mass spectrometry and NGS experiments that identified a set of proteins and RNA markers
that have been validated by multiple experiments in vitro and in a few pilot patient cohorts, as explained in
preliminary results. In this application, we will employ innovative technologies to translate our efforts to define
LO-based signatures to the CLIA laboratory to determine clinical utility of our liquid biopsy approach in PC
patients with lethal disease, both in the castration resistant and hormone sensitive space. We will leverage an
expansive cohort of clinically annotated PC specimens (N=600), both retrospectively and prospectively collected
from 2 independent sites. In Aim 1, we will perform analytical validation of LO isolation technologies for clinical
use. In Aim 2, we will develop an LO-centered multianalyte assay to detect lethal PC and predict ARSI response.
In Aim 3 we will assess the sensitivity and specificity of PLUS in metastatic hormone-sensitive PC patients to
predict lethal outcomes. We will continue to focus on PC because of the significance of PC open clinical
questions, of the challenges relative to this tumor-type in liquid biopsy development, and our extensive
experience in the field of PC molecular landscape. Yet, there is great opportunity for our LO-based assay to be
expanded to other tumor types in the future. Our study is technologically innovative and will likely result in the
identification of new markers and ultimately in the application of a microfluidic device to the CLIA lab. The M-PI
team brings expertise not only on EVs (Di Vizio, Stott, Demichelis), but also on ctDNA (Demichelis) and CTCs
(Stott) and propose orthogonal approaches to determine which method, among bead-based and microfluidic
capture, which will be benchmarked against density gradients, has the best performance in a complex clinical
lab.
Terms: <Address><Androgenic Agents><Androgenic Compounds><Androgens><Assay><Base of Human Prostate><Base of the Prostate><Benchmarking><Best Practice Analysis><Bioassay><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Tests><Body Tissues><Cancer Patient><Cancers><Castrate sensitive prostate cancer><Castration><Cell Communication and Signaling><Cell Signaling><ChIP assay><Circulation><Clinical><Communities><Complex><DNA Methylation><Data><Data Set><Deposit><Deposition><Development><Disease><Disorder><Elements><Endocrine Gland Secretion><Evaluation><Evolution><Future><Genomics><Goals><Gold><HLA-DR Associated Protein II><Hematologic Tests><Hematological Tests><Hematology Testing><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hormones><IGAAD><In Vitro><Inhibitor of GZMA-Activated DNase><Intracellular Communication and Signaling><Laboratories><Lipoproteins><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Metastatic Prostate Cancer><Methods><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Molecular><NGS Method><NGS system><Non-Polyadenylated RNA><Outcome><Patients><Performance><Phenotype><Phosphatase 2A Inhibitor I2PP2A><Plasma><Plasma Serum><Population><Prostate CA><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Proteins><Protocol><Protocols documentation><Quality Control><RNA><RNA Gene Products><RNA marker><Research Specimen><Resistance><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Running><SET Translocation Inhibitor-2 of Protein Phosphatase-2A><Sampling><Sensitivity and Specificity><Set protein><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Specimen><Structure of base of prostate><Surgical Castration><Technology><Template Activating Factor I Beta><Testing><Therapeutic Androgen><Therapeutic Hormone><Tissues><Transcript><Translating><Tumor Cell><Tumor-Derived><Validation><Work><androgen sensitive prostate cancer><benchmark><bio-informatics pipeline><bioinformatics pipeline><biological signal transduction><biomarker identification><blood cancer><cancer of blood><cancer of the blood><cancer sub-types><cancer subtypes><chromatin immunoprecipitation><circulating biomarkers><circulating markers><clinical translation><clinically translatable><cohort><density><deprivation><developmental><experience><experiment><experimental research><experimental study><experiments><expression subtypes><extracellular vesicles><hormone sensitive prostate cancer><identification of biomarkers><identification of new biomarkers><inhibitor><innovate><innovation><innovative><innovative technologies><liquid biopsy><malignancy><marker identification><microfluidic chip><microfluidic technology><minimally invasive><molecular sub-types><molecular subsets><molecular subtypes><neoplasm/cancer><neoplastic cell><new marker><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel biomarker><novel marker><particle><pressure><prospective><protein biomarkers><protein markers><resistant><response><response to therapy><response to treatment><therapeutic response><therapy response><treatment response><treatment responsiveness><tumor><validations><µfluidic><µfluidic technology>